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EMBO Rep. 2013 Jan;14(1):49-56. doi: 10.1038/embor.2012.189. Epub 2012 Nov 30.

Structural basis of ligand recognition in 5-HT3 receptors.

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1
Laboratory of Structural Neurobiology, KULeuven, Leuven, Belgium.

Abstract

The 5-HT(3) receptor is a pentameric serotonin-gated ion channel, which mediates rapid excitatory neurotransmission and is the target of a therapeutically important class of anti-emetic drugs, such as granisetron. We report crystal structures of a binding protein engineered to recognize the agonist serotonin and the antagonist granisetron with affinities comparable to the 5-HT(3) receptor. In the serotonin-bound structure, we observe hydrophilic interactions with loop E-binding site residues, which might enable transitions to channel opening. In the granisetron-bound structure, we observe a critical cation-π interaction between the indazole moiety of the ligand and a cationic centre in loop D, which is uniquely present in the 5-HT(3) receptor. We use a series of chemically tuned granisetron analogues to demonstrate the energetic contribution of this electrostatic interaction to high-affinity ligand binding in the human 5-HT(3) receptor. Our study offers the first structural perspective on recognition of serotonin and antagonism by anti-emetics in the 5-HT(3) receptor.

PMID:
23196367
PMCID:
PMC3537142
DOI:
10.1038/embor.2012.189
[Indexed for MEDLINE]
Free PMC Article
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